Drug Helps in Two Types of Pulmonary Hypertension

by John Gever John Gever Senior Editor, MedPage Today
October 24, 2012

Action Points

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Explain that riociguat, a novel pulmonary vasculature relaxant, significantly improved 6-minute walk distances in two placebo-controlled trials in patients with different types of pulmonary hypertension.

Note that patients with both pulmonary arterial hypertension or inoperable chronic thromboembolic pulmonary hypertension seemed to benefit from riociguat with an increase in hypotension but not in syncope.

ATLANTA -- Treatment with a first-in-class drug called riociguat was effective against two types of pulmonary hypertension, according to phase III study results presented here.

Riociguat, which relaxes pulmonary blood vessels via a novel mechanism, improved 6-minute walk distances in patients with pulmonary arterial hypertension (PAH) and in those with chronic thromboembolic pulmonary hypertension (CTEPH) in separate placebo-controlled trials, according to Hossein Ardeschir Ghofrani, MD, of University Hospital of Giessen and Marburg in Giessen, Germany, who led both studies.

Ghofrani told attendees at a late-breaking abstract session at the American College of Chest Physicians (ACCP) meeting that the drug is likely to be effective in all forms of pulmonary hypertension, despite their different etiologies.

"At a certain level of severity, they have commonalities" that would make a single drug helpful, he suggested.

Riociguat stimulates the soluble guanylate cyclase enzyme, which partners with nitric oxide to regulate vascular tone. It appears to be relatively selective for pulmonary vessels, as it usually does not induce large drops in systemic blood pressure.

Ghofrani noted that in addition to the phase III trials in PAH and CTEPH, the drug has shown promise in initial studies involving other forms of pulmonary hypertension that stem from left ventricular dysfunction, emphysema, and interstitial lung disease.

Top-line data from the PAH study were released at the start of the meeting by riociguat's developer, Bayer HealthCare. The main result was that the drug improved 6-minute walk distances by a mean of 36 meters relative to placebo in the trial, dubbed PATENT-1.

More Data on PATENT-1 Trial

In his formal presentation, Ghofrani fleshed out those data with additional details. The study randomized 443 patients to three study arms, with 254 assigned to riociguat at doses up to 2.5 mg three times daily, 126 to placebo, and 63 to an exploratory riociguat arm in which the maximum dose was 1.5 mg three times daily.

Only the first two arms were included in the analysis reported by Ghofrani.

He said that baseline 6-minute walk distances averaged about 365 meters, meaning that the relative improvement of 36 meters in the 12-week study worked out to about a 10% increase.

Other, secondary efficacy outcomes were as follows, expressed as the difference relative to placebo:

Pulmonary vascular resistance: -27% (P<0.0001)

Mean pulmonary arterial pressure: -7% (P=0.0002)

NT-proBNP: -38% (P<0.0001)

Ghofrani also reported that 21% of PAH patients taking riociguat improved in WHO functional class, compared with 14% of the placebo group. At the other end, 3% of the riociguat group showed worsening versus 14% of the placebo group (P=0.0033).

General quality of life scores showed a nonsignificant trend toward better improvement with the active drug, but a 14% improvement relative to placebo in a disease-specific quality of life scale did reach significance (P=0.0019).

Riociguat was not without its adverse effects. Some 27% of patients taking the drug reported headaches, 19% had dyspepsia, 17% developed peripheral edema, 16% felt nauseated or dizzy, and 14% suffered diarrhea -- all more frequently than in the placebo group.

Also, 10% of the riociguat group developed hypotension, compared with 2% of the placebo group. Ghofrani said that the hypotension "was largely asymptomatic." Syncope, which was also of special interest in the trial, was not more common with riociguat than with placebo.

Although CTEPH is less common than PAH, it also represents an important potential target for riociguat because there are currently no approved drug therapies for the condition.

Ghofrani said the standard of care for CTEPH currently is surgical intervention, which is not appropriate for patients with distal emboli and is not always effective in patients eligible for such procedures.

CHEST-1 Trial Results

In the second phase III riociguat trial reported at the meeting, called CHEST-1, 261 patients were recruited at numerous sites around the world who were either ineligible for surgery (as determined by an independent panel of endovascular surgeons) or had recurrent or persistent pulmonary hypertension after a surgical intervention.

These patients were randomized in a 2:1 ratio to riociguat at doses up to 2.5 mg three times daily or placebo.

In both the CHEST-1 and PATENT-1 trials, drug doses were titrated upward from a starting dose of 1 mg three times over an 8-week period to maintain a stable, relatively normal peripheral blood pressure.

Systolic pressure was measured every two weeks. Drug doses were increased by 0.5 mg when the pressure was 95 mm Hg or higher, left alone if pressure was in the range of 90 to 94 mm Hg, or decreased by 0.5 mg if pressure was less than 90 mm Hg. In patients with pressures below 90 mm Hg who also had symptoms of hypotension, dosing was halted for a day and then restarted at a lower dose.

Doses at the end of the 8-week titration period were then maintained for an additional 12 weeks.

As in PATENT-1, the primary endpoint in CHEST-1 was the change relative to placebo in 6-minute walk distance at the end of 12 weeks.

That endpoint was met in near-spectacular fashion, Ghofrani reported, with a relative mean improvement of 46 meters from a mean at baseline of about 350 meters.

The improvement was somewhat greater in patients ineligible for surgery (54 meters) -- about two-thirds of the whole sample -- compared with the surgery-refractory patients (27 meters). The difference in the latter subgroup relative to placebo did not reach statistical significance.

Also as in PATENT-1, riociguat was significantly effective according to most secondary endpoints in the CTEPH patients, including pulmonary vascular resistance, NT-proBNP, and WHO functional class change.

The adverse event profile was similar in CHEST-1 as well, including the increased rate of hypotension -- also characterized by Ghofrani as "largely asymptomatic" -- and with no difference in syncope episodes.

Both the PAH and CTEPH trials included open-label extension phases, named PATENT-2 and CHEST-2, respectively, in which the initial placebo groups were allowed to receive the active drug under the same titration protocol, and the former active-drug groups continued on their former doses but with a sham titration phase.

Ghofrani said both studies were still underway, but he showed preliminary data from those patients who had received riociguat in the randomized phases.

In both the PAH and CTEPH studies, continued treatment led to further improvements in 6-minute walk distances, adding another 10 to 20 meters over 12 weeks of additional treatment, which were then maintained for a full year.

Full results from the extension studies are to reported next year, Ghofrani said.

Bayer has said it plans to submit marketing applications for riociguat early next year as well.

Bayer funded both studies and two of the investigators were Bayer employees.

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